Post on 29-May-2020
transcript
Updates in Indolent Lymphoma
Sameer Mahesh
Hematology-Oncology
Summa Cancer Institute
• No disclosures or conflicts of interest
Overview
• Follicular Lymphoma: Initial treatment
Relapsed disease
• Lymphoplasmacytic Lymphoma/Waldenstrom’s Macroglobulinemia
• Hairy Cell Leukemia
Follicular Lymphoma- Case 1
68 male presents in 2011 with fatigue, enlarged lymph nodes in neck and axilla
Excision biopsy of axillary lymph node shows Follicular Lymphoma grade 1-2/3
CT scan of Chest/Abd/Pelvis shows enlarged lymph nodes in the chest, axilla, upper abdomen, and pelvis (> 4 areas)
Blood counts normal. Hemoglobin 13. LDH 280 (elevated)
Bone marrow biopsy shows presence of FL (30%) marrow
Follicular Lymphoma- Case 1 (contd)
FLIPI score (Follicular Lymphoma International Prognostic Index)
Age > 60 (yes)
LDH (lactate dehydrogenase) > upper limit of normal (yes)
Hemoglobin > 12 (no)
Ann Arbor Stage III or IV (yes)
Number of involved areas > 4 (yes)
FLIPI high risk ( has 4/5) factors
Follicular Lymphoma- Case 1 (contd)
• Does the patient need treatment: Yes. He has symptoms
Treatment: He was placed on ECOG 2408 study. Phase 2 three arm study
BR R maintenance
BVR R maintenance
BR R + L maintenance
B (Bendamustine, TREANDA); R (Rituximab, RITUXAN)
V (Bortezomib, VELCADE); L (Lenalidomide, REVLIMID)
Follicular Lymphoma- Case 1 (contd)
• He was randomized to BR R maintenance arm
• Received 6 cycles of BR. Tolerated well. Enlarged lymph nodes normalized clinically and on imaging. Bone marrow cleared.
• Tolerated rituximab maintenance well (borderline white count which improved once rituximab completed)
• Continues to be in complete remission
Discussion points
• Symptoms indicating immediate treatment (fever, night sweats, weight loss, fatigue, bothersome lymphadenopathy, low blood counts)
• What is initial frontline treatment in high FLIPI score FL (role of bendamustine)
• Role of lenalidomide
• Role of maintenance rituximab after chemotherapy
Role of bendamustine
German NHL1 study 514 patients with FL, iNFL (indolent non follicular lymphoma) and MCL
BR RCHOP 94% overall response rate 94% 40% complete response rate 30% 70 progression free survival (months) 31 0% alopecia when 3 or more cycles 100% 37% infections 60% 7% peripheral neuropathy 29% 30% hematologic toxicity 68% 6% mouth sores 19% 16% rash/skin reactions 9%
Role of bendamustine BRIGHT Study
BR RCHOP RCVP 97% Response Rate 92% 31% Complete Response 25% 4% Alopecia 50%/21% 12% Peripheral neuropathy 45% 22% Rash 14%
Role of Lenalidomide
• Oral immunomodulator
• FDA approved for multiple myeloma, a subtype of MDS and mantle cell lymphoma
• Has single agent activity but exciting in combination with rituximab
• M.D. Anderson study had 110 patients (FL 50). Overall response rate was 98% and complete response rate 87%.
• Significant adverse effects (neutropenia, rash, muscle pain, cough, dyspnea, faitigue, thrombosis)
• RELEVANCE: Ongoing phase 3 studies assessing R2 versus R-chemo (STAY TUNED!)
Rituximab maintenance after R-chemotherapy
PRIMA study 1019 patients randomized after initial treatment with RCHOP, RCVP, or RFND
Rituximab once every Observation 2 months x 2 years 75% 3 year progression free survival 57% 39% Infections 24%
Follicular Lymphoma Case 2
• 46 female presented in 2012 with cervical lymphadenopathy of 3 months duration. No fever, B symptoms. Otherwise asymtomatic
• Hemoglobin 13; LDH 180
• CT C/A/P neck, upper abdominal lymphadenopathy (max size 3 cm)
• Bone marrow biopsy (10% involvement by FL)
Follicular Lymphoma Case 2
FLIPI score (Follicular Lymphoma International Prognostic Index)
Age > 60 (no)
LDH (lactate dehydrogenase) > upper limit of normal (no)
Hemoglobin > 12 (no)
Ann Arbor Stage III or IV (yes)
Number of involved areas > 4 (no)
FLIPI Low risk (1 risk factor) category
Follicular Lymphoma Case 2
• Management: Watchful waiting
Rituximab single agent
Rituximab with chemotherapy
• Options 1 and 2 discussed.
• Sought 2nd opinion. Discussed 1,2 and 3
• Patient elected to do single agent rituximab
Follicular Lymphoma Case 2
• She received weekly rituximab x 4
• Lymph nodes resolved clinically and on imaging
• Continues to do well.
• Follows up every 4 months for history and physical and blood count
Discussion points
• Watch and wait versus treat?
• Maintenance rituximab after single agent rituximab
UK Study 379 patients low tumor burden FL in UK, Aus, NZ, Poland and Turkey
Watch & Wait Rituximab Rituximab weekly x 4 weekly x 4 every 2mo x 12 ARM CLOSED
Number not needing treatment at 3 yrs 46% 88%
RESORT Study (E4402) Previously untreated low tumor burden FL received rituximab x 4
Responders
Rituximab re-treatment Rituximab maintenance Treatment at time of Once every 3 months progression till progression 3.9 yrs Time to treatment failure 4.3 yrs 84% 3 year freedom from cytotoxic therapy 95% 4 Median number of rituximab doses 18
Relapsed/ Refractory Disease
• Idelasib (Zydelig) a PI3Kδ inhibitor most recent drug to be approved
• PI3Kδ highly expressed in hematologic cell surface and is important in conducting signals that allow normal cell development and function.
• Hyperactive in B cell cancers making it an attractive target
Relapsed/ Refractory Disease
• Study 101-09 included 125 patients with indolent lymphoma that were refractory to rituximab and chemotherapy
• Median number of previous regimens was 4
• Overall response rate 57% (6% complete response)
• Median time to response was 2 months and duration was 12.5 months
• Diarrhea (43%/13%), neutropenia (56%/27%), liver enzyme elevation (40%/10%),
• Pneumonia 10%
CALGB 50401
Phase 2 study of relapsed lymphoma more than 6 months after last rituximab treatment 94 patients
Lenalidomide Lenalidomide + Rituximab 49% Response Rate 75% 14 months Progression free survival 24 months
GADOLIN 396 patients with rituximab refractory iNHL. Patients had received average of 2 prior therapies
Bendamustine Bendamustine + obinutuzumab 63% Response Rate 69% 14 mo Progression free survival 29 mo 63% ≥ grade 3 adverse events 69%
Waldenstrom’s Macroglobulinemia
• WM is an indolent B-cell lymphoma associated with clonal lymphoplasmacytic cells and monoclonal IgM secretion
• Current active drugs used in 1st line settings include cyclophosphamide, steroids, bortezomib, bendamustine, rituximab. Fludarabine that was used previously is not go-to drug anymore
• First line treatment is highly active with durable responses. However, relapses do occur and approach to treatment is on the lines of other iNHL
• Ibrutinib ( BTK-bruton tyrosine kinase) inhibitor approved for CLL, relapsed MCL and relapsed Waldenstrom’s Macroglobulinemia
Waldenstrom’s Macroglobulinemia
• 63 patients with WM that received at least 1 prior treatment received ibrutinib at 420mg daily
• Overall response 90%; major response 73%
• At 2 years, 69% were estimated to be progression free and 90% expected to be alive
• Neutropenia and thrombocytopenia were main adverse effects
Hairy Cell Leukemia
• HCL is a chronic, indolent B-cell cancer characterized by low blood counts (and its complications) and enlarged spleen
• Treatment is initiated at onset of symptoms or when counts significantly low
• Purine analogues (cladribine and pentostatin) and used in first line setting. Appx 30-50% relapse and with retreatment (rituximab also used in retreatment setting) duration of response will shorten and/or bone marrow reserve declines due to stem-cell toxic nature of the above drugs
• BRAF V600E mutation is seen in almost 100% of HCL cases making drugs that target the above mutation potential treatment options
Vemurafinib in HCL
• Vemurafinib is an oral BRAF inhibitor
• Patients with relapsed/refractory HCL to purine analogues were treated with vemaurafinib 960mg twice a day
• 2 studies were conducted. One in Italy and other in US
• Overall response rates were 96% and 100% respectively
• Complete responses were 35% and 42% respectively
• Average relapse free time was 19 months for patients with CR and 6 months in patients with partial response.
• Thank you for your attention!
• Questions